tbuckley/cabot-search huggingface dataset:
Acalabrutinib in patients with relapsed/refractory (R/R) marginal zone lymphoma (MZL): Results of a phase 2, multicenter, open-label trial.
Authors: L Elizabeth Budde, Morton Coleman, Don A. Stevens, Shuo Ma, Caterina Patti, M. Yair Levy, Izidore S. Lossos, Praveen Ramakrishnan Geethakumari, Selay Lam, Roser Calvo, Kara Higgins, Paolo Strati
Journal: Journal of Clinical Oncology (2022)

7549 Background: MZL is a rare indolent B-cell malignancy considered incurable at recurrent stage. Bruton tyrosine kinase (BTK) inhibitors have produced durable responses in patients (pts) with R/R MZL. Acalabrutinib (acala) is a potent next-generation BTK inhibitor with high selectivity for BTK. We report data for acala monotherapy from the R/R MZL cohort (phase 2) of a phase 1b/2 clinical trial (NCT02180711). Methods: Pts with histologically confirmed MZL, ECOG performance status ≤2, and ≥1 prior therapy (including ≥1 CD20-directed regimen) received oral acala 100 mg twice daily until disease progression or unacceptable toxicity ± R. The primary objective was overall response rate (ORR; Lugano criteria as assessed by the investigator). Secondary objectives were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Data were analyzed descriptively (no formal hypothesis testing). Results: Forty-two pts received acala (median age 69 y [range 42–84]; median 2 prior systemic regimens [range 1–4]). MZL subtypes were extranodal (43%), nodal (31%), and splenic (26%). At data cutoff (Oct 15, 2021), median follow-up duration was 10.7 mo (range 0.4–42.8). Sixteen (38%) pts discontinued acala, most commonly due to disease progression (26%). Among pts evaluable for response (n = 37; 3 pts had not reached the first assessment timepoint and 2 pts exited the study without response assessment), ORR was 54% (95% CI 37%–71%) with 6 complete (16%) and 14 partial (38%) responses; 17 (46%) pts had stable disease. ORRs in extranodal, nodal, and splenic subtypes were 65%, 44%, and 45%, respectively. Median time to initial response was 3.0 mo; median DOR was 19.3 mo (95% CI 8.4–not estimable). Median PFS was 27.4 mo with a 12-mo PFS rate of 66%. Four pts died (disease progression, n = 2; transformation to diffuse large B-cell lymphoma after stopping treatment, n = 1; adverse event [AE], n = 1 [septic shock unrelated to treatment]); median OS was not reached. Treatment was well tolerated with most AEs being grade 1 or 2. Sixteen pts (38%) had grade ≥3 AEs, most commonly (in ≥2 pts) anemia, dyspnea, neutrophil count decrease (n = 3 each), fatigue, thrombocytopenia, and neutropenia (n = 2 each). AEs led to treatment discontinuation in 2 pts (grade 3 hypotension and grade 1 myalgia). Among AEs of clinical interest, hypertension was reported in 2 pts (both grade 2); no cases of atrial fibrillation/flutter or major hemorrhage were reported. Conclusions: These early results indicate that acala is efficacious and well tolerated in pts with R/R MZL. The AE profile is consistent with the known safety profile of acala. Clinical trial information: NCT02180711.
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) versus intravenous chemotherapy in unresectable peritoneal metastases secondary to platinum-resistant ovarian cancer: Interim analysis of Indian randomized control trial.
Authors: S.P. Somashekhar, Rohit Kumar, Amit Rauthan, Poonam Patil, Priya Kapoor, Susmita Rakshit, Ashwin K. Rajgopal
Journal: Journal of Clinical Oncology (2022)

5524 Background: PIPAC has emerged as a novel way to deliver intraperitoneal chemotherapy. PIPAC has shown improved response rate and quality of life in patients with inoperable peritoneal carcinomatosis. Methods: The trial is registered with Clinical Trials Registry – India (CTRI) REF/2018/08/021223. Interim analysis is presented here. Primary endpoint was to assess the objective response rate (With RECIST 1.1) between PIPAC and IV chemotherapy arm. Secondary endpoints were to assess quality of life (QLQ C-30) and morbidity (CTCAE 4.0 and Clavien dindo) between the two groups. PIPAC was done with dose of cisplatin 15mg /m2 and doxorubicin at 3mg/m2. The choice of chemotherapy was left at the discretion of treating physician. The response rate (With MRI &amp; Ca-125) &amp; quality of life assessment (QLQ C-30) of both the group was done periodically and recorded. Results: 40 patients underwent 105 PIPAC applications with nearly 25 (62.5%) had 3 cycles completed. 40 patients underwent IV chemotherapy same time with nearly 23 (57.5%) having received atleast 5 cycles. Mean age 57.3±8.05, PCI 24.45±6.39, with nearly 45.5% of patients had previous surgery and 72.5% of patients having received atleast 2 lines of prior chemotherapy and nearly 60 % having ascites. The objective response rate is 66.6% versus 22.5%, grade 3-4 events were 10.0% vs. 35.7 % in PIPAC and IV arm respectively. Histological regression was seen in 67.5% of patients with 3 cycles PIPAC. Functional, symptom and global health score at day 120 was significantly better with PIPAC arm when compared to IV arm. Conclusions: PIPAC is safe and feasible for patients with unresectable platinum resistant ovarian cancer. PIPAC showed better objective response rates and improved quality of life when compared to chemotherapy arm with acceptable morbidity. Clinical trial information: REF/2018/08/021223.
Inherited TNFSF9 deficiency causes broad Epstein–Barr virus infection with EBV+ smooth muscle tumors
Authors: Benjamin Fournier, Akihiro Hoshino, Julie Bruneau, Camille Bachelet, Mathieu Fusaro, Roman Klifa, Romain Lévy, Christelle Lenoir, Claire Soudais, Capucine Picard, Stéphane Blanche, Martin Castelle, Despina Moshous, Thierry Molina, Anne-Sophie Defachelles, Bénédicte Neven, Sylvain Latour
Journal: The Journal of Experimental Medicine (2022)

Epstein–Barr virus (EBV) can infect smooth muscle cells causing smooth muscle tumors (SMTs) or leiomyoma. Here, we report a patient with a heterozygous 22q11.2 deletion/DiGeorge syndrome who developed a unique, broad, and lethal susceptibility to EBV characterized by EBV-infected T and B cells and disseminated EBV+SMT. The patient also harbored a homozygous missense mutation (p.V140G) in TNFSF9 coding for CD137L/4-1BBL, the ligand of the T cell co-stimulatory molecule CD137/4-1BB, whose deficiency predisposes to EBV infection. We show that wild-type CD137L was up-regulated on activated monocytes and dendritic cells, EBV-infected B cells, and SMT. The CD137LV140G mutant was weakly expressed on patient cells or when ectopically expressed in HEK and P815 cells. Importantly, patient EBV-infected B cells failed to trigger the expansion of EBV-specific T cells, resulting in decreased T cell effector responses. T cell expansion was recovered when CD137L expression was restored on B cells. Therefore, these results highlight the critical role of the CD137–CD137L pathway in anti-EBV immunity, in particular in the control of EBV+SMT.
MEDB-17. Re-irradiation for recurrent medulloblastoma in a matched cohort: Advantageous especially in patients without resection
Authors: Jonas E Adolph, Stephan Tippelt, Sebastian Tschirner, Christine Gaab, Ruth Mikasch, Martin Mynarek, Stefan Rutkowski, Monika Warmuth-Metz, Brigitte Bison, Stefan M Pfister, Olaf Witt, Torsten Pietsch, Rolf-Dieter Kortmann, Stefan Dietzsch, Beate Timmermann, Gudrun Fleischhack
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Radiotherapy with craniospinal irradiation (CSI) is an important part of initial treatment for medulloblastoma in most children. Radiotherapy after recurrence is currently not widely used. This analysis aims to evaluate whether re-irradiation (RT2) may show survival benefits. METHODS: Data for patients with recurrent medulloblastomas from the German HIT-REZ studies was gathered. Patients with RT2 at 1st recurrence were matched by propensity score to an equal number of patients without radiotherapy. Matching variables were sex, initial therapy, time to recurrence, metastatic stage and therapy at 1st recurrence and radiotherapy at subsequent recurrences. The matched cohort was analysed regarding PFS and OS after 1st recurrence. RESULTS: From a cohort of 240 pre-irradiated patients, 106 patients were matched. Patients with RT2 showed improved median PFS [21.0 months (95%-CI: 17.5 – 27.6)] and OS [37.5 months (CI: 30.0 – 59.4)] compared to control patients [(PFS: 12.0 months (CI: 8.1 – 17.7) / OS: 20.1 months (CI: 14.5 – 44.8)]. When stratifying by resection at recurrence (36.8% resected), a survival advantage for RT2 was found in patients without resection in PFS [19.6 (CI: 14.9 – 31.5) vs. 8.0 months (CI: 5.4 – 14.4)] and OS [41.9 (CI: 30.0 – 59.4) vs. 13.3 months (CI: 8.1 – 36.7)]. However, no advantage was found after resection [PFS: 22.5 (CI: 17.5 – 50.4) vs. 19.1 months (CI: 14.1 – 34.3) / OS: 32.3 (CI: 27.6 – NA) vs. 48 months (CI: 23.4 – NA)]. CSI was used in 6 patients without differences in survival to focal RT2. Median PFS after first irradiation was 32.5 months, after RT2 20.9 months. No patients with RT2 were alive past 10 years after 1st recurrence.CONCLUSION: Patients with recurrent medulloblastoma show benefits from RT2 in median PFS and OS. However, no advantage for RT2 was found when resection was also applied at recurrence. Cure after treatment with RT2 was not found in our cohort.
Prostate cancer prediction using classification algorithms.
Authors: Xingyue Huo, Joseph Finkelstein
Journal: Journal of Clinical Oncology (2022)

e13590 Background: The object of this study was to evaluate the efficacy of machine learning classification algorithms for prostate cancer prediction using patients' age, CCI score, and medical procedures. Methods: We analyzed a dataset of 112,605 individuals from the IBM MarketScan database between 2016 and 2019, deviding them into two groups based on whether they diagnosis with prostate cancer in 2019. Then we retrospectively reviewed these subjects' medical records including the CCI, medical procedure records and ages. Machine learning classifiers consisting of support vector machine (SVM), decision tree (DT), random forest (RF), Extreme Gradient Boosting (XGBoost), and adaptive boosting (Adaboost) were used to analyze the prediction accuracy of prostate cancer. For all machine learning prediction models, 70% of the randomly chosen data samples were used for training, and 30% were used as a test set. The classifier with the highest accuracy were selected for prediction and identify feature importance. Results: The study included 112,605 subjects, of which 19,564 (17.4%) men who diagnosed with prostate cancer in 2019. Overall, The best prediction model for prostate cancer prediction was XGBoost, with the cancer prediction accuracy in the test set of 84%. The “Minor male genital procedures” was the highest scored feature importance, while age is not an important feature in prostate cancer prediction among elderly males. Conclusions: The more urethral/male genital examination procedures an individual has received in the past two years, the more attention should be paid to the risk of having prostate cancer. These results suggest that the analysis of individual medical records using machine learning classification algorithms can increase the prediction rate of prostate cancer.
Comparative effectiveness analysis of oncological and functional outcomes after salvage radical treatment with surgery or radiotherapy following primary focal or whole-gland ablative therapy for localised prostate cancer
Authors: A. Nathan, A. Ng, A. Mitra, R. Davda, P. Sooriakumaran, S. Patel, M. Fricker, J. Kelly, G. Shaw, P. Rajan, A. Sridhar, S. Nathan, H. , Payne
Journal: European Urology (2022)
A single institution cohort of patients with classical Hodgkin lymphoma treated with brentuximab vedotin plus nivolumab.
Authors: Aryanna Jordan, Ashley Rose, Alizain Bangash, Leidy Lismeri Isenalumhe, Sameh Gaballa, Julio C. Chavez, Bijal D. Shah, Lubomir Sokol, Javier Pinilla-Ibarz, Celeste M. Bello, Hayder Saeed
Journal: Journal of Clinical Oncology (2022)

e18738 Background: Classical Hodgkin lymphoma (cHL) is a B-cell neoplasm which affects approximately 8,500 new patients annually. The initial remission rate is greater than 80%; however, 10-30% will have refractory or relapsed disease (R/R). Both Brentuximab vedotin (BV) and nivolumab (Nivo) have recently been approved for the treatment of R/R cHL. Previous studies have shown BV+Nivo to be well tolerated, with high response rates and progression free survival (PFS) in two prospective studies. However, no real-world data is available yet for this combination. Here we present clinical characteristics and outcomes of a single institution cohort of patients with cHL who received BV+Nivo. Methods: A retrospective chart review was completed of all patients with cHL who were treated with BV+Nivo at Moffitt Cancer Center between 2018 and 2021. Baseline characteristics and treatment details were obtained. PFS and overall survival (OS) were evaluated using the Kaplan-Meier curve. Results: A total of 29 patients were included in the cohort. Median follow up time was 3 months (range 1-21). 69% (n = 20) of patients were male. Histology types included unclassifiable 48.3% (n = 14), nodular sclerosis 27.6% (n = 8), lymphocyte depleted 13.8% (n = 4), and lymphocyte rich 10.3% (n = 3). 55.2% (n = 16) of patients had B symptoms at presentation. Initial stage included stage 2 (48.3%, n = 14), stage 3 (20.7%, n = 6), and stage 4 (24.1%, n = 7). 34% of the patients were primary refractory to their first line therapy. Median time from last chemo to BV+Nivo was 4.4 months (range 0.5-50 months). BV+Nivo was most often used as 2 nd line therapy (51.7%, n = 15) followed by 3 rd line therapy (20.7%, n = 6). One patient received BV+Nivo as first line therapy. Median number of cycles was 4 (range 1-15). The overall response rate was 65.5% (n = 19) (complete response 44.8%), and 17.2% (n = 5) had no response. Of the 15 patients receiving BV+Nivo as 2nd line therapy, 66% proceeded to autologous hematopoietic stem cell transplant. 4 patients did not proceed with transplant per their choice, and one patient could not proceed due to progressive disease. The median PFS was 21 months (95% CI: 9 months-non reached). OS was 100%. Conclusions: Here we describe the first real-world outcomes of BV+Nivo in classical Hodgkin lymphoma. In a high risk and refractory population, BV+Nivo showed excellent responses. Further studies are needed to focus on comparing the outcome to a more traditional chemotherapy based approach.
The mammalian SKIV2L RNA exosome is essential for early B cell development
Authors: Kun Yang, Jie Han, Jennifer G. Gill, Jason Y. Park, Meghana N. Sathe, Jyothsna Gattineni, Tracey Wright, Christian Wysocki, M. Teresa de la Morena, Nan Yan
Journal: Science Immunology (2022)

The SKIV2L RNA exosome is an evolutionarily conserved RNA degradation complex in the eukaryotes. Mutations in the
Real-life adverse events related to PDE-5 I treatment: Analysis of the EudraVigilance database
Authors: R. Lombardo, A. Nacchia, A. Cicione, B. Turchi, G. Gallo, A. Guercio, J. Stira, L. Rovesti, A. Franco, C. Gravina, G. Guarnotta, E. Mancini, O.A. Voglino, V. Baldassarri, S. D'Annunzio, S. Riolo, A. Tubaro, C. De Nunzio
Journal: European Urology (2022)
MEDB-71. Molecular characterisation of group 4 medulloblastoma improves risk-stratification and its biological understanding
Authors: Jack Goddard, Jemma Castle, Emily Southworth, Anya Fletcher, Stephen Crosier, Idoia Martin-Guerrero, Miguel Garcia-Ariza, Aurora Navajas, Julien Masliah-Planchon, Franck Bourdeaut, Christelle Dufour, Tobias Goschizk, Torsten Pietsch, Stacey Richardson, Rebecca M Hill, Daniel Williamson, Simon Bailey, Edward C Schwalbe, Steven C Clifford, Debbie Hicks
Journal: Neuro-Oncology (2022)

Abstract Group 4 (MBGrp4) accounts for ~40% of medulloblastoma and the majority of non-WNT/non-SHH cases, yet its underpinning biology is poorly understood, and survival outcomes are not sufficiently explained by established clinico-pathological risk factors. We investigated the clinical and molecular correlates of MBGrp4, including second-generation methylation non-WNT/non-SHH subtypes (I-VIII) and whole chromosome aberration (WCA) subtypes (defined by chromosome 7 gain, 8 loss, and 11 loss; WCA-favourable risk [WCA-FR] ≥2 features, WCA-high risk [WCA-HR] ≤1 feature). A clinically-annotated MBGrp4 discovery cohort (n=378) was assembled from UK CCLG institutions, collaborating centres and SIOP-UKCCSG-PNET3/HIT-SIOP-PNET4 clinical trials. Contemporary molecular profiling integrating methylation/WCA subtypes and next-generation sequencing was performed. Survival modelling was carried out with patients &amp;gt;3 years old who received craniospinal irradiation (n=336). Association analysis confirmed relationships between methylation and WCA subtypes. Subtypes VI and VII were enriched for WCA-FR (p&amp;lt;0.0001) and aneuploidy, whereas subtype VIII was defined solely by i17q (p&amp;lt;0.0001). Whilst we observed an overall low mutational burden, WCA-HR harboured recurrent mutations in genes involved in chromatin remodelling (p=0.007). No gene-specific events were associated with disease risk, however integration of both methylation subtype and WCA groups enabled improved risk-stratification survival models that outperformed current schemes. The optimal MBGrp4-specific model stratified patients into: favourable-risk (local disease, subtype VII or subtype VI with WCA-FR; 39/194 [20%], 97% 5-year PFS), very-high-risk (metastatic disease with WCA-HR; 71/194 [37%], 50% 5-year PFS) and high-risk (remaining patients; 84/194 [43%], 67% 5-year PFS). Findings were validated in independent cohorts. Comprehensive clinico-molecular assessment of MBGrp4 provides important understanding of its clinical and biological heterogeneity. Our novel MBGrp4 stratification scheme removes standard risk disease and identifies a favourable risk group (20% of MBGrp4) with potential for therapy de-escalation. Current therapeutic strategies are insufficient for the very-high risk group (encompassing 37% of MBGrp4), for whom novel therapies are urgently required.
End-of-life care for patients with advanced ovarian cancer in the Netherlands: A retrospective registry-based analysis.
Authors: Esther Broekman, Maaike Van Der Aa, Hans Nijman, Mathilde Jalving, An K.L Reyners
Journal: Journal of Clinical Oncology (2022)

e17612 Background: Patients with advanced ovarian cancer have a poor prognosis and can experience debilitating abdominal symptoms in the last phase of life. Several analyses, mainly performed in the United States (US), show high rates of chemotherapy administration, and emergency room and hospital visits near the end-of-life in this patient category. No large European studies are available, while the organisation of palliative care differs between the US and Europe and between European countries. We aimed to analyse the intensity of inpatient care near the end-of-life in the Netherlands and perform a cross-study comparison with previous reports. Methods: All patients with ovarian cancer that died in 2016 and 2017 were identified from the database of the foundation Dutch Hospital Data (DHD). For the last six months of life the following parameters of aggressive care were extracted: administration of chemotherapy, emergency room (ER) visits, surgical procedures, hospital and intensive care unit (ICU) admissions. Data were analysed for the cohort as a whole and separately for three age categories: &lt; 60, 60-75 and &gt; 75 years of age. The intensity of inpatient care was compared to previously reported European and US data. Results: A total of 2172 patients died with ovarian cancer in 2016 and 2017 in the Netherlands. Data on medical care use was available for 1775 patients. During the last 6 months of life, chemotherapy was given to half of the ovarian cancer patients and the same percentage of patients was admitted to hospital. Chemotherapy administration near the end-of-life was infrequent, with only 12% of patients receiving chemotherapy in the last month of life. Surgery and ICU admissions in the final 6 months of life were rare (&lt; 10%). Our cohort showed the lowest percentages of all five indicators of aggressive care reported thus far. The use of chemotherapy in the six months prior to death was highest in patients 60-75 years of age compared to younger or older patients. ER visits and hospital admissions were less frequent in patients &gt; 75 years of age compared to the younger age groups. Conclusions: Aggressive medical care use in the final 6 months of life in this Dutch cohort of ovarian cancer patients was lower than in other previously reported cohorts.
ETMR-02. Overexpression of Lin28A in neural progenitor cells in vivo does not lead to brain tumor formation but results in reduced spine density
Authors: Maximilian Middelkamp, Lisa Ruck, Christoph Krisp, Piotr Sumislawski, Behnam Mohammadi, Matthias Dottermusch, Valerie Meister, Lukas Küster, Hartmut Schlüter, Sabine Windhorst, Julia E Neumann
Journal: Neuro-Oncology (2022)

Abstract The RNA binding protein LIN28A is a stem- and progenitor marker and one of the factors necessary to induce pluripotent stem cells. An overexpression of LIN28A has been identified in malignant brain tumors called embryonal tumors with multilayered rosettes (ETMR) but its specific role during brain development remains largely unknown. Radial glia cells of the ventricular zone (VZ) are proposed as a cell of origin for ETMR. We asked whether an overexpression of LIN28A in such cells might affect brain development or result in the formation of brain tumors. Constitutive overexpression of LIN28A in hGFAP-cre::lsl-Lin28A (GL) mice led to a transient increase of proliferation in the cortical VZ at embryonic stages but no postnatal brain tumor formation. Postnatally, GL mice displayed a pyramidal cell layer dispersion of the hippocampus and altered spine and dendrite morphology, including reduced dendritic spine densities in the hippocampus and cortex. GL mice displayed hyperkinetic activity and differential quantitative MS-based proteomics revealed altered time dependent molecular functions regarding mRNA processing and spine morphogenesis. Phosphoproteomic analyses indicated a downregulation of mTOR pathway modulated proteins such as Map1b being involved in microtubule dynamics within a crosstalk of Gsk3b/Rho-Rac/Map1b signaling. In conclusion, we show that Lin28A overexpression transiently increases proliferation of neural precursor cells but it is not sufficient to drive brain tumors in vivo. In contrast, Lin28A impacts on protein abundancy patterns related to spine morphogenesis and phosphorylation levels of proteins involved in microtubule dynamics, resulting in decreased spine densities of neurons in the hippocampus and cortex as well as in altered behavior. Our work provides new insights into the role of LIN28A for neuronal morphogenesis and development and may reveal future targets for treatment of ETMR patients.
Impact of disease status heterogeneity of the STAMPEDE trial arm J population on oncological outcomes in high-risk nonmetastatic prostate cancer
Authors: S. Hatakeyama, T. Tanaka, D. Noro, T. Okamoto, T. Narita, N. Ishi, R. Tanaka, T. Oishi, H. Miura, C. Ohyama
Journal: European Urology (2022)